The major zones of skin are the epidermal and dermal regions, with various appendages such as hair follicles, sweat glands, and sebaceous glands. The outermost layer of the skin is called the stratum corneum and is a part of the epidermis. The stratum corneum forms the barrier that keeps water in and unwanted materials out of the body. Below the stratum corneum lies the viable epidermis, which consists of 10 cell layers. The epidermis is viable tissue made up primarily (about 90-95%) of keratinocytes. Three substrata of living cells in the skin are the basal, spinous, and granular layers. These three layers provide progressive stages of differentiation and keratinization of the living keratinocytes as they move toward the skin's surface to become part of the stratum corneum.
Melanocytes synthesize the yellow, red, and brown biochromesmelanin, which are large polymers bound to proteins. Melanin is made by the melanocytes in membrane bound organelles called melanosomes. Melanocytes form a network of cells near the basal layer of stratum germinatium. Melanin absorbs light over a broad range of wavelengths (200-2400 nm), thus serving as an excellent screen against the damaging cutaneous effects of solar ultraviolet radiation. During a process termed “melanization”, melanosomes are transferred from the melanocytes to the keratinocytes.
Derivatives of melatonin have antioxidant activity. Anti-oxidant activity may occur (a) through direct free radical scavenging and/or (b) through up-regulation of genes involved in the anti-oxidant response. Compounds which exert their antioxidant activity only through direct free radical scavenging exert an acute effect, which is limited by the half life of the compound, whereas compounds which exert their antioxidant effect through gene regulation potentially have a much longer term of effect. Mammalian cells possess signaling mechanisms that control the cells' ability to metabolize electrophiles, for example by induction of phase II enzymes such as glutathione transferase, through antioxidant/electrophile response elements (ARE) in their regulatory sequences. These antioxidant response elements are not inducible by reactive oxygen species (ROS) per se; however, a set of genes are induced in response to ROS exposure and help the cell deal with oxidative damage by controlling cell proliferation and DNA/protein repair processes, largely independent of those associated with the antioxidant response.
Reactive oxygen species (ROS) are constitutively produced in epidermal keratinocytes by specific processes, such as enzymatic oxidations and aerobic respiration. In addition, ROS can be induced by several cytokines, growth factors, and other physiological stimuli. Skin damage caused by ultraviolet (UV) radiation is also associated with ROS.
After prolonged exposure, the UV part of sunlight can cause significant damage to skin. The solar UV radiation that reaches the earth's surface is comprised of two components: UVB at a wavelength of 280-320 nm and UVA at a wavelength of 320-380 nm. UVA is weakly absorbed by most biomolecules, it is absorbed in the skin by melanin and hemoglobin, but is oxidative in nature. The oxidative nature of the UVA radiation absorbed by the melanin and hemoglobin leads to the generation reactive oxygen species. Furthermore, there is evidence from under vacuum studies that irradiation of macromolecules with UVA radiation can cause generation of hydrogen peroxide (H202) and that iron-catalyzed reduction of H202 by superoxide anion can further generate the highly reactive hydroxyl radical (OH−).
Likewise, high doses of UVB also generate hydroxyl radicals (OH−) and lead to DNA damage. Meanwhile, high levels of superoxide dismutase (SOD) in cells may protect the cells against UVB radiation. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathiond reductase (GSH-Rd) are antioxidant enzymes in human cells. These enzymes are important in cellular defense against UV-induced oxidative stress. Oxidative stress of non-differentiated keratinocytes triggers the formation of a defective horny layer, the key mechanism of psoriasis.
Melatonin is a free radical scavenger. Besides OH−, 02− and ROO−, melatonin neutralizes nitric oxide (NO), peroxynitrite anion and hypochlorous acid. Melatonin also activates antioxidative enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Rd).
By scavenging 02−, melatonin reduces the formation of ONOO− and prevents the activation of poly(ADP-ribose)synthase. Melatonin also curtails the synthesis of NO, thereby reducing the formation of ONOO−. Moreover, melatonin scavenges ONOO− and OH− directly. Since the over-production of ROS contributes to acute inflammatory response, small molecules which permeate biological membranes and function as intracellular radical scavengers, such as melatonin, may be useful in the therapy of conditions associated with local or systemic inflammation.
Oxidative stress has been linked to inflammatory skin diseases, such as psoriasis, and skin diseases could result from an imbalance between pro-oxidant and antioxidant stimuli. Cytokines and growth factors can act to stimulate, specifically, the generation of superoxide anion (02−) and hydrogen peroxide (H202), which act as second messengers in modulating the redox status of individual components of the signaling pathways. The individual components thusly modulated include growth factor receptors and transcription factors. The excessive generation of 02− and H2O2 may be sufficient to propel the cellular redox balance to a more pro-oxidant state that favors oxidative damage and an apoptotic pathway.
UV radiation induces the generation of free radicals in biological tissues, such as skin. Among these free radicals, the superoxide anion (02−) and the highly toxic hydroxyl radical (OH−) cause tissue damage by reacting with biomolecules, such as lipids and proteins, and result in the formation of lipid peroxides.
Melatonin is an active participant in the antioxidative defense system of an organism. Studies suggest that melatonin is protective against free radical damage at physiological concentrations and is readily absorbed when administered via any route. Melatonin has proved effective in reducing oxidative damage in conditions where free radical involvement has been established, such as ionizing radiation. Resisting free radical damage is a feature of melatonin and melatonin can protect against a wide range of radical and reactive species damage.
It is believed that melatonin is an antioxidative protective agent against DNA damage and lipid peroxidation in vitro and in vivo. The mechanisms of melatonin inhibition of lipid peroxidation include the direct scavenging of the initiating radicals, especially OH−1 and ONOO−. Furthermore, a possible relationship exists between psoriasis, ROS, melatonin and its derivatives.
Moreover, indoles have long been known to possess chemical antioxidant properties and to protect against carcinogenesis. These functions have been attributed to the ability of indoles to react with free radicals and electrophiles. All indoleamines share a hetero-aromatic ring system of high electron-reactivity and only differ in the functional groups appended in the side chains. These side chains determine to a great extent the reactivity potency and efficiency of radical scavenging.
Consumers have long desired cosmetic and pharmaceutical compositions which provide cosmetically or pharmaceutically effective treatment or protection from the effects of free radicals. In response to this desire, antioxidants have been formulated through the years to protect from or prevent the harm associated with free radicals. Although melatonin is a radical scavenging agent, the reaction of melatonin and its analogues with ROS have not been fully studied, nor have the effects of melatonin or its metabolites and analogues upon psoriasis been evaluated. Similarly, there currently does not exist a satisfactory antioxidant derived from melatonin that provides all of the needed protection from the harmful effects of free radicals.
For this reason, there is a need in the art for compounds and compositions of melatonin derivatives which will adequately protect from the harmful effects of free radicals. The present subject matter addresses this need.